KR20100024963A - A transition metal catalyzed synthesis of 2h-indazoles - Google Patents

Abstract

The present invention relates to a process for the regioselective synthesis of compounds of the formula (I), wherein R0; R1; R2; R3; R4; R5; A1; A2; A3; A4; Q and J have the meanings indicated in the claims. The present invention provides a direct transition metal catalyzed process to a wide variety of multifunctional 2H-indazoles or 2H-azaindazoles of the formula (I) from 2-halo-phenylacetylenes or (2-sulfonato)phenylacetylenes and monosubstituted hydrazines, useful for the production of pharmaceuticals, diagnostic agents, liquid crystals, polymers, herbicides, fungicidals, nematicidals, parasiticides, insecticides, acaricides and arthropodicides.

Description

A transition metal catalyzed synthesis of 2H-indazoles

The present invention relates to a method for the selective selective synthesis of a compound of formula (I) which is useful as an intermediate for preparing useful pharmaceutically active ingredients.

In Formula I above,

R0, R1, R2, R3, R4, R5, A1, A2, A3, A4, Q and J are as defined below.

The present invention provides for the preparation of various polyfunctional substituted 2H-indazoles or substituted 2H-azindaazoles of formula (I) from 2-halo-phenylacetylene or (2-sulfonato) phenyl-acetylene and monosubstituted hydrazines. A direct transition metal catalyzed method.

Indazoles exhibit a wide range of biological activities and can be regarded as important structures in pharmaceutical research. The ability of the indazole backbone to mediate interactions with various biological targets is not only due to the large number of reports on observed biological activity, but also that some indazole-based compounds may be an important component of the pharmaceutically active ingredient in which the heterocycle is useful. The data is well documented by the fact that it is being developed or marketed as an indication drug. Some examples of biological activity include anti-inflammatory activity (see RJ Steffan, E. Matelan, MA Ashwell, WJ Moore, WR Solvibile, E. Trybulski, CC Chadwick, S. Chippari, T. Kenney, A. Eckert). L. Borges-Marcucci, JC Keith, Z. Xu, L. Mosyak, DC Harnish J. Med. Chem. 2004, 47, 6435-38).

Of course, the use of indazole or azaindazole is not limited to the pharmaceutical uses described above. For example, indazole can be used in countless other applications, for example, in particular plant growth regulators (Y. Kamuro, K. Hirai Chemical Regulation of Plants, 1982, 17, 65) or liquid crystals (C. Canlet, MA Khan, BM Fung, F. Roussel, P. Judeinstein, J.-P. Bayle New.J. Chem. 1999, 23, 1223).

Indazole exists in three isomeric forms as 1H-, 2H-, and 3H-indazole, depending on the substitution pattern of the heterocyclic ring, and development of 1H-indazole has been made through a number of synthesis, but 2H- There is no general protocol for synthesizing indazoles.

Known methods for preparing substituted 2H-indazole or substituted 2H-aza indazole by direct N-arylation or N-alkylation (see JJ Song, NK Yee, Org. Lett., Vol. 2, No. 4, 2000, 519-521; LD Shirtcliff, TR Weakley, MM Haley, F. Kohler, R. Herges J. Org. Chem ,, 2004, 69, 6979-85, inevitably have poor selectivity N ( A mixture of 1) and N (2) regioisomers is provided. The few methods available to date are often poor in efficiency as they are low yield and multi-step methods that provide a limited range of substrate selectivities, thus limiting their use but suffer from the same limitations as the existing processes mentioned above.

Although numerous transition metal catalysis protocols for intermolecular cross-coupling between aryl halides and amides, amines, hydrazides and hydrazones have been reported, only three examples using hydrazines exist. Buchwald et al. Described mono-substituted hydrazines, 1,1-disubstituted hydrazines and 1, using palladium catalysts in toluene and tert-butoxide bases to obtain moderate to good yields of the desired arylated hydrazine. Some examples of crosscoupling between 2-disubstituted hydrazine and aryl bromide are described (SL Buchwald, S. Wagaw, O. Geis WO 99/43643). A similar catalytic system for cross-coupling aryl bromide with 1,1-dialkyl-substituted hydrazine- (LiCl ₂ ) ₂ adducts in good yields has been reported by Cacchi et al. (See S. Cacchi). , G. Fabrizi, A. Goggiamani, E. Licandro, S. Maiorana, D. Perdicchia Org. Lett. 2005, 2, 1497-1500). Vasilevsky and Prikhodko provided 1H-indazole in good yield using hydrazine in cross-coupling reactions with (2-chloro-5-nitrophenyl) arylacetylene. TA Prikhodko, SF Vasilevsky Russ. Chem. Bull.Int.Ed., 2001, 50, 1268-1273). The reaction proceeds by a palladium catalyzed domino coupling-closing reaction, the reaction range being somewhat limited in that only four examples are reported and only (2-chloro-5-nitrophenyl) arylacetylene is used. . In addition, in the same relationship, Basilevsky and Precodeco also palladium catalyzed dominoes of 2-iodoarylhydrazine and 4-nitrophenyl-acetylene to provide 4-nitrobenzyl-1H-indazole in low yields. Report a single example of Sonogashira-closure reaction. A single example of forming 2H-indazole in 30% yield by the same domino sonogashra-ring-closure reaction between N '-(2-iodophenyl) acetic hydrazide and 4-nitrophenylacetylene is also described above. It is described in.

It has now been found that the disadvantages mentioned can be avoided by direct, catalytic, gentle and various regioselective synthesis.

The object of the present invention is achieved by starting from 2-halo-phenylacetylene or (2-sulfonate) phenyl-acetylene of formula II and monosubstituted hydrazine of formula III in the presence of a transition metal catalyst.

[Summary of invention]

The present invention provides a broad range of multifunctional substituted 2H-indazole or substituted 2H-aza of formula (I) starting from 2-halo-phenylacetylene or (2-sulfonate) phenylacetylene of formula (II) and monosubstituted hydrazine of formula (III). Provides a direct transition metal catalyzed synthetic route to indazole.

An advantage of the methods provided above is that the methods include direct, catalytic, mild and various methods for the synthesis of substituted 2H-indazoles or substituted 2H-azidadazoles. Since the multistage reaction proceeds as a single vessel domino reaction sequence using only a single catalyst, the process is very time and cost efficient as well as environmentally friendly. In addition, the reaction conditions are compatible with a wide variety of functional groups and a wide variety of starting materials to ensure the universality of the reaction.

1) The present invention provides a process for preparing a compound of formula (I) by reacting a compound of formula (II) with a compound of formula (III) or any salt thereof in the presence of a transition metal catalyst and optionally allowing the compound of formula (I) to be physiologically acceptable Of all stereoisomeric forms of the compounds of formula (I) and / or compounds of formula (I), and / or mixtures of all proportions of these forms and / or physiologically acceptable salts of compounds of formula (I), comprising converting to salts It relates to a manufacturing method.

Formula I

In the above formulas (I), (II) and (III),

A1, A2, A3 and A4 are each independently selected from a carbon atom or a nitrogen atom, and together with two carbon atoms in the formula (I) form a stable aromatic or heteroaromatic ring,

Q is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-substituted, di- or tri-substituted independently of one another by R 14; -(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13; - (C ₁ -C ₄₎ - alkylene -O- (C ₁ -C ₄₎ - alkylene; - (C ₁ -C ₄₎ - alkylene -O-; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, and

J is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; -(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, and

R0, R1, R2, R3 and R4 are the same or different independently of each other,

a) hydrogen atom,

b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted 1 to 3 times by R 13,

c) halogen,

d) phenyloxy-, wherein the phenyloxy is unsubstituted or substituted one to three times by R13;

_{e) - (C 1 -C 3} ) - alkyl, fluoroalkyl,

f) -N (R 10)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13,

g)-(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

h) — (C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di-, tri-, or tetra-substituted independently of one another by R 13,

i)-(C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

j) 3- to 7-membered cyclic moieties containing one, two, three or four heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other by R13. Mono-, di-, tri- or tetra-substituted),

k) -O-CF ₃ ,

l) —O— (C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13;

m) -NO ₂ ,

n) -CN,

o) -OH,

p) -C (O) -R10,

q) -C (O) -O-R11,

r) -C (O) -N (R11) -R12,

s) -N (R11) -R12,

t) -N (R10) -SO ₂ -R10,

u) -S-R10,

v) -SO _n -R 10, where n is 1 or 2,

w) -SO ₂ -N (R11) -R12 or

x) -O-SO ₂ -R13

y) when at least one of A1, A2, A3 or A4 is a nitrogen atom, at least one of R1, R2, R3 or R4 is absent,

A 5 member containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen together with the atoms to which R1 and R2, R2 and R3 or R3 and R4 are attached Or an 8-membered ring, wherein said ring is unsubstituted or mono-, di-, tri- or tetra-substituted by R 14, and

R5 is

a)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13;

b) halogen,

c) phenyloxy-, wherein said phenyloxy is unsubstituted or substituted one to three times by R13;

_{d) - (C 1 -C 3} ) - alkyl, fluoroalkyl,

e) -N (R10) - ( C 1 -C 4) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13),

f)-(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

g)-(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

h) — (C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

i) 3- to 7-membered cyclic moieties containing one, two, three or four heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other by R13 Mono-, di-, tri- or tetra-substituted),

j) -O-CF ₃ ,

_{k) -O- (C 1 -C 4} ) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13),

l) -NO ₂ ,

m) -CN,

n) -OH,

o) -C (O) -R10,

p) -C (O) -O-R11,

q) -C (O) -N (R11) -R12,

r) -N (R11) -R12,

s) -N (R10) -SO ₂ -R10,

t) -S-R10,

u) -SO _n -R 10, where n is 1 or 2,

v) -SO ₂ -N (R11) -R12 or

w) -O-SO ₂ -R13,

R 10 is a hydrogen atom, — (C ₁ -C ₃ ) -fluoroalkyl or — (C ₁ -C ₆ ) -alkyl,

R11 and R12 are the same or different independently from each other,

a) hydrogen atom,

b)-(C ₁ -C ₆ ) -alkyl, wherein said alkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13,

c)-(C ₆ -C ₁₄ ) -aryl-, wherein the aryl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13; or

d)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13, and

R 13 is halogen, —NO ₂ , —CN, ═O, —OH, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, -CF ₃ , phenyloxy-, -C ( O) -R10, -C (O) -O-R17, -C (O) -N (R17) -R18, -N (R17) -R18, -N (R10) -SO ₂ -R10, -S- R 10, -SO _n -R 10, wherein n is 1 or 2, -SO ₂ -N (R 17) -R 18,-(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or substituted for R 14 Mono-, di-, or tri-substituted independently from each other),-(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is unsubstituted or mono-, di-, or trisubstituted independently of one another by R14 ,-(C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14, or a heteroatom selected from nitrogen, sulfur or oxygen 1 Three to seven membered cyclic moieties containing dogs, two, three or four, wherein the cyclic moieties are unsubstituted or poisoned with each other by R14 Typically one is substituted, disubstituted or tri-substituted),

R14 is halogen, -OH, = O, -CN, -CF ₃ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ , -C (O) -OH , -N (R11) -R12, -C (O) -O- (C 1 -C 4) - _{alkyl, - (C 1 -C 8)} - alkylsulfonyl, -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N-[(C ₁ -C ₈ ) -alkyl] ₂ , -C (O) -NH ₂ , -S-R 10, -N (R 10) -C _{(O) -NH- (C 1 -C} 8) - and - [alkyl _{(C 1 -C 8) -]} 2, alkyl, or -N (R10) -C (O) -N

R17 and R18 are the same or different independently of each other,

a) hydrogen atom,

_{b) - (C 1 -C 6} ) - alkyl,

c)-(C ₆ -C ₁₄ ) -aryl- or

d)-(C ₅ -C ₁₄ ) -heteroaryl,

X is Cl, Br, I, triflate, nonaplate, tosylate, alkyl sulfonate or aryl sulfonate.

2) The present invention also,

A 1, A 2, A 3 and A 4 together with the two carbon atoms in formula I form benzene, pyrazine, pyridazine, pyridine, pyrimidine, triazine or tetraazine,

Q is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₆ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; Phenyl, wherein said phenyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13; - (C ₁ -C ₄₎ - alkylene _{- O- (C 1 -C 4)} - alkylene; - (C ₁ -C ₄₎ - alkylene -O-; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is acridinyl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, aze Thidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH Carbazolyl, carbolinyl, chromanyl, chromenyl, cinnaolinyl, decahydrocinnolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo [1,3,4] oxathiazinyl, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydro Furanyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indanyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isobenzofuranyl , Iscro Neyl, Isoindazolyl, Isoindolinyl, Isoindolinyl, Isoquinolinyl, Isothiazolyl, Isothiazolidinyl, Isothiazolinyl, Isoxazolyl, Isoxazolinyl, Isoxazolidinyl, 2- Isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadizolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 , 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepi Neyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phena Genyl, Phenothiazinyl, Phenoxatiinyl, Phenoxazinyl, Phtharazinyl, Piperazinyl, Piperidinyl, Pterridinyl, Furinyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolyl , Pyrazolo [3,4-b] pyridine, pyridazinyl, pyri Oxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quino Nolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, Tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thia Diazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazoli Denyl, thiazolinyl, thienyl, thiethanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4 -Triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein said heteroaryl is unsubstituted or independently of one another by R13 mono-, di-, tri- or Is substituted)

J is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₆ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; Phenyl, wherein said phenyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as defined above and is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

R0, R1, R2, R3 and R4 are the same or different independently of each other,

a) hydrogen atom,

b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted 1 to 3 times by R 13,

c) F, Cl or Br,

d) phenyloxy-, wherein the phenyloxy is unsubstituted or substituted once, twice or three times by R13,

_{e) - (C 1 -C 3} ) - alkyl, fluoroalkyl,

f) -N (R10) - ( C 1 -C 4) - alkyl (wherein the alkyl is unsubstituted or substituted once by R13, 2 times or 3 times),

g) phenyl or naphthyl, wherein said phenyl or naphthyl is unsubstituted or mono-, di- or tri-substituted by R13

h) — (C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is as defined above and is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

i)-(C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

j) azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirin, di Oxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, Isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4- Oxazane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxetane, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole , Pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine , Thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thia Gin, 1,3-thiazole, thiazole, thiazolidine, thiazolin, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, Selected from 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13 3-7 membered cyclic residues,

k) -O-CF ₃ ,

l) —O— (C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted once, twice or three times by R 13,

m) -CN,

n) -OH,

o) -C (O) -R10,

p) -C (O) -O-R11,

q) -C (O) -N (R11) -R12,

r) -N (R11) -R12,

s) -N (R10) -SO ₂ -R10,

t) -S-R10,

u) -SO _n -R 10, where n is 1 or 2,

v) -SO ₂ -N (R11) -R12,

w) -O-SO ₂ -R13 or

x) when at least one of A1, A2, A3 or A4 is a nitrogen atom, one of R1, R2, R3 or R4 is absent,

R5

a)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted once, twice or three times by R13,

b) F, Cl or Br,

c) phenyloxy-, wherein said phenyloxy is unsubstituted or substituted once, twice or three times by R13,

_{d) - (C 1 -C 3} ) - alkyl, fluoroalkyl,

e) -N (R10) - ( C 1 -C 4) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13),

f) phenyl or naphthyl, wherein said phenyl or naphthyl is unsubstituted or mono-, di- or tri-substituted by R13,

g)-(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is as defined above and unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13,

h) — (C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13,

i) azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirin, di Oxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, Isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4- Oxazane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxetane, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole , Pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine , Thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-ti Gin, 1,3-thiazole, thiazole, thiazolidine, thiazolin, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, Selected from 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13 3-7 membered cyclic residues,

j) -O-CF ₃ ,

_{k) -O- (C 1 -C 4} ) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13),

l) -CN,

m) -OH,

n) -C (O) -R10,

o) -C (O) -O-R11,

p) -C (O) -N (R11) -R12,

q) -N (R11) -R12,

r) -N (R10) -SO ₂ -R10,

s) -S-R10,

t) -SO _n -R 10, where n is 1 or 2,

u) -SO ₂ -N (R11) -R12 or

v) -O-SO ₂ -R13,

R 10 is a hydrogen atom, — (C ₁ -C ₃ ) -fluoroalkyl or — (C ₁ -C ₆ ) -alkyl,

R11 and R12 are the same or different independently from each other,

a) hydrogen atom,

b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13,

c) phenyl, wherein said phenyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R13; or

d)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as defined above and is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 13,

R13 is F, Cl, -CN, = O, -OH,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, -CF ₃ , phenyloxy-, -C (O) -R10, -C (O) -O-R17, -C (O) -N (R17) -R18, -N (R17) -R18, -N (R10) -SO ₂ -R10, -S-R10, -SO _n -R10 where n is 1 or 2, -SO ₂ -N (R17) -R18, phenyl, wherein the phenyl is unsubstituted or is mono-, di- or trisubstituted independently of each other by R14 -(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is as defined above and is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14,-(C _3- C ₆ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by R 14, or a 3-7 membered cyclic moiety wherein said cyclic moiety is Unsubstituted or mono-, di-, or tri-substituted independently of one another by R14), and

R14 is F, Cl, -OH, = O, -CN, -CF ₃ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -C (O) -OH,- N (R11) -R12, -C ( O) -O- (C 1 -C 4) - _{alkyl, - (C 1 -C 8)} - _{alkylsulfonyl, -C (O) -NH 2,} -C ( _{O) -NH- (C 1 -C 8} ) - alkyl, -C (O) -N - [ (C 1 -C 8) - _{alkyl] 2, -S-R10, -N} (R10) -C (O ) -NH- (C ₁ -C ₈ ) -alkyl or -N (R 10) -C (O) -N [(C ₁ -C ₈ ) -alkyl] ₂ ,

R17 and R18 are the same or different independently of each other,

a) hydrogen atom,

_{b) - (C 1 -C 4} ) - alkyl,

c) phenyl or

d)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as defined above,

And X is Cl, Br, I, triflate, nonaplate, tosylate, alkyl sulfonate or aryl sulfonate.

3) The present invention

A 1, A 2, A 3 and A 4 together with the two carbon atoms in formula I form benzene or pyridine,

Q is a covalent bond; - (C ₁ -C ₆₎ - alkylene; -(C ₃ -C ₆ ) -cycloalkyl; Phenyl, wherein said phenyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13; - (C ₁ -C ₄₎ - alkylene -O- (C ₁ -C ₄₎ - alkylene; - (C ₁ -C ₄₎ - alkylene -O-; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is selected from pyridyl, quinolinyl, tetrahydropyranyl and thienyl,

J is a covalent bond; - (C ₁ -C ₆₎ - alkylene; -(C ₃ -C ₆ ) -cycloalkyl; Phenyl; Naphthyl; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as described above,

R0, R1, R2, R3 and R4 are the same or different independently of each other,

a) hydrogen atom,

b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one, two or three times by R 13,

c) F, Cl or Br,

d) naphthyl, wherein said naphthyl is unsubstituted or substituted once, twice or three times by R13,

e) phenyl, wherein the phenyl is unsubstituted or substituted once, twice or three times by R13,

f)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as described above,

g)-(C ₃ -C ₆ ) -cycloalkyl,

_{h) -O- (C 1 -C 4} ) - alkyl,

i) -CN,

j) -OH,

k) -C (O) -R10,

l) -C (O) -O-R11,

m) -C (O) -N (R11) -R12,

n) -N (R11) -R12 or

p) -O-SO ₂ -R13,

R5

a)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted once, twice or three times by R13,

b) F, Cl or Br,

c) naphthyl, wherein said naphthyl is unsubstituted or substituted once, twice or three times by R13,

d) phenyl, wherein the phenyl is unsubstituted or substituted once, twice or three times by R13,

e)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as described above,

f)-(C ₃ -C ₆ ) -cycloalkyl,

_{g) -O- (C 1 -C 4} ) - alkyl,

h) -CN,

i) -OH,

j) -C (O) -R10,

k) -C (O) -O-R11,

l) -C (O) -N (R11) -R12,

m) -N (R11) -R12 or

n) -O-SO ₂ -R13,

R 10 is hydrogen or — (C ₁ -C ₄ ) -alkyl,

R11 and R12 are the same or different independently from each other, and are a hydrogen atom or-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or mono-, di- or tri-substituted independently from each other by R13 ,

R 13 is F, Cl, —CN, —OH, — (C ₁ -C ₄ ) -alkoxy, —CF ₃ or phenyl, wherein the phenyl is unsubstituted or mono-, di- or tri-substituted independently of each other by R 14 )

R14 is F, Cl, -OH, -CN, -CF ₃ ,-(C ₁ -C ₄ ) -alkyl or-(C ₁ -C ₄ ) -alkoxy,

A process for the preparation of compounds of formula (I) wherein X is Cl, Br, I or tosylate.

The reaction can be carried out in a wide range of protic or aprotic solvents, including polar aprotic solvents and even in some cases without solvents. Examples of such solvents are tert-butanol, benzene, toluene, xylene, mesitylene, acetonitrile, propionitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, N, N-dimethylformamide, N-methylpy Rollidinone, N, N-dimethylacetamide, dimethylsulfoxide, 1,2-dimethoxyethane, tert-butylmethylether, triethylamine, diisopropylethylamine or pyridine. N, N-dimethylacetamide, N, N-dimethylformamide and N-methylpyrrolidinone are preferable. Most preferred is N, N-dimethylformamide.

Bases useful in the process of the invention are basic organic or inorganic compounds which act as proton acceptors without inhibiting the catalytic activity of the transition metal catalysts used. Suitable classes of such bases are, for example, carbonates, phosphates, alkoxides, hydroxides, amides and hydrides with suitable metals or alkali metals as counterions. Carbonates and phosphates are preferred bases in the process of the invention. Potassium carbonate or potassium phosphate and especially cesium carbonate are preferred bases. The base can be used in pure form or a mixture of several bases can be used.

The base is generally used in an appropriate excess based on 2-halo-phenylacetylene or (2-sulfonate) phenylacetylene of formula II. Useful ranges are from 0.5 to 10 fold excess based on 2-halo-phenylacetylene or (2-sulfonate) phenylacetylene of formula II. A more useful range is 1.1 to 2.0 fold excess based on 2-halo-phenylacetylene or (2-sulfonate) phenylacetylene of formula II. The base is preferably used in a 1.4-fold excess based on 2-halo-phenylacetylene or (2-sulfonate) phenylacetylene of formula II. In reactions in which the hydrazine is used as a salt, for example as a hydrochloride salt, an additional 1 equivalent of base is added to the reaction mixture relative to the added salt to produce the hydrazine in situ. Alternatively, when the hydrazine is used as the corresponding amide prepared by the reaction of the hydrazine or the hydrazine salt with a strong base, the reaction can be carried out without a base.

The active form of the transition metal catalyst is not known. Therefore, the term “transition metal catalyst” in the present invention refers to any catalytic transition metal and / or active form of catalyst which promotes any portion of the reaction as well as the catalyst precursor which is introduced into the reaction vessel and converted into the active form in situ. Include. The transition metal catalyst may be used in any amount, but generally 0.00005 to 90 mol% will be used. Preferably from 0.01 to 20 mol%, even more preferably from 0.5 to 10 mol%, most preferably from 1 to 5 mol% of a transition metal catalyst is used.

In general, any suitable transition metal catalyst capable of mediating the reaction can be used, which includes lanthanide elements as well as group 3 to 12 elements of the periodic table. Preferred transition metals include platinum, palladium, nickel, gold, copper, iron, ruthenium, rhodium and iridium. Nickel and palladium are even more preferred, and palladium is most preferred. The transition metal catalyst may be soluble or insoluble and certain sources of transition metals useful in this process include Pd-halides, Pd-halide complexes, Ni-halides, Ni-halide complexes, Pd-phosphine complexes, Ni-forces. Pin complex, Pd-alkene complex, Ni-alkene complex, Pd-alkanoate, Pd-alkanoate complex, Pd-acetonate, Ni-alkanoate, Ni-alkanoate complex, Ni-acetonate, Rani Nickel, Pd / C or Ni / C, or polymer supported palladium or nickel species or mixtures thereof, but is not limited thereto. Representative examples include palladium (II) chloride, palladium (II) bromide, palladium (II) iodide, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, palladium (II) trifluoroacetate , Tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, bis (dibenzylideneacetone) palladium (0), bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) Palladium (0), nickel (II) chloride, nickel (II) bromide, nickel (II) iodide, Ni (acac) ₂ , Ni (1,5-cyclooctadiene) ₂ , aceto (2′-di- Tert-butylphosphino-1,1'-biphenyl-2-yl) palladium (II), (1,2-bis (diphenylphosphino) ethane) dichloropalladium (II), bis [1,2- Bis (diphenylphosphino) ethane] palladium (0), [(2S, 3S) -bis (diphenylphosphino) butane] [eta3-allyl] palladium (II) perchlorate, 1,3-bis (2,4 , 6-trimethylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) pal Rhodium (0) dimer, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl include palladium (II) chloride, but is not limited this.

Preferred transition metal sources are palladium (II) chloride, palladium (II) bromide, palladium (II) iodide, tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, palladium (II) trifluoro Loacetate, tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, bis (dibenzylideneacetone) palladium (0), bis (triphenylphosphine) -palladium (II) chloride, tetrakis (tri Phenylphosphine) palladium (0), even more preferred is palladium (II) chloride, palladium (II) bromide, palladium (II) iodide, tris (dibenzylideneacetone) dipalladium (0). Most preferred palladium sources are palladium (II) chloride and tris (dibenzylideneacetone) dipalladium (0).

Groups of ligands useful in the present invention may be chelated or unchelated, and may be alkyl or aryl phosphines or mixtures thereof, such as dicyclohexylphenylphosphine, or aryl or alkyl diphosphines or mixtures thereof, Diamines, imines, heterocyclic carbenes or hybrids thereof.

The ligands can be used in free form or as salts, for example hydrochloride or tetrafluoroborate salts.

For illustrative purposes only, the ligand may be selected from, but is not limited to, the following compounds: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate salt, tricyclohexylphosphine , Dicyclohexylphenylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, trimethylphosphine, triethylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2 ', 4', 6'- Triisopropyl-1,1'-biphenyl, 2,2'-bis (di-tert-butylphosphino) biphenyl, (+/-)-2,2'-bis (diphenylphosphino)- 1,1'-Vinaphthalene, (9,9-dimethyl-9h-xanthene-4,5-diyl) bis [diphenyl phosphine], (R)-(-)-1-[(S) -2 -(Diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, (R)-(-) -1-[(S) -2- (dicyclohexylphosphino) ferrocenyl] -ethyldi-tert-butylphosphine, (R)-(+)-1,1'-bis (diphenylphosphino) ) -2,2'-bis (N, N-diisopropylamido) ferrocene, (S, S) -1- [1- (di-tert-butylphosphino) ethyl] -2- (diphenyl Phosphino) ferrocene, (1R, 2R)-(+)-1,2-diaminocyclohexane-N, N'-bis (2-diphenylphosphino-1-naphthoyl, (-)-1,2 -Bis ((2S, 5S) -2,5-diisopropylphosphorano) -benzene, bis [(2-diphenylphosphino) phenyl] ether, (S)-(-)-2,2'- Bis (di-para-tolylphosphino) -1,1'-binafil, 4,5-bis (bis (3,5-bis (trifluoromethyl) phenyl) -phosphino) -9,9-dimethyl Xanthene.

Preferred ligands are tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate salt, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ', 4', 6'-tri Isopropyl-1,1'-biphenyl. More preferred ligands are tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate salts and most preferred are tri-tert-butylphosphine tetrafluoroborate salts.

Most preferably, tri-tert-butylphosphine or tri-tert-butylphosphine tetrafluoroborate is a palladium source that does not contain the phosphine itself, in particular palladium (II) chloride, palladium (II) ) Bromide, palladium (II) iodide, or (dibenzylideneacetone) dipalladium (0)].

The ligand may be used in any amount, but generally 0.00005 to 90 mol% will be used. Preferably from 0.01 to 40 mol%, even more preferably from 0.5 to 20 mol% and most preferably from 1 to 10 mol% of the ligand is used. The ratio of ligand to transition metal is generally about 1 to 20, preferably about 1 to 5, most preferably 2.

The reaction step is usually carried out in a temperature range of 0 to 300 ℃, preferably 25 to 150 ℃, most preferably 80 to 130 ℃. In general, the reaction is carried out at atmospheric pressure, excluding air and moisture, such as under an inert atmosphere (eg argon or nitrogen atmosphere). The reaction time is in the range of 2 to 48 hours (h).

The progress of the reaction can be monitored by methods known to those skilled in the art, for example thin layer silica gel chromatography, gas chromatography, nuclear magnetic resonance, infrared spectrometer, and high pressure liquid chromatography combined with ultraviolet or mass spectrometer. have. Preferably, thin layer silica gel chromatography and high pressure liquid chromatography (HPLC) in combination with a mass spectrometer are used.

Useful separations and purifications for the compounds obtained by the process of the invention include, for example, filtration through cartridge containing celite, aqueous workup, extraction with organic solvents, distillation, crystallization, chromatography on silica, and normal Or well known to those skilled in the art, such as high pressure liquid chromatography on reverse phase. Preferred methods include, but are not limited to, these examples.

The term alkyl, as used herein, explicitly includes unsaturated groups as well as unsaturated groups, which unsaturated groups contain one or more, for example one, two or three double bonds and / or triple bonds. All of these descriptions also apply when the alkyl group appears as a substituent in another moiety, for example an alkyloxy moiety, an alkyloxycarbonyl moiety or an arylalkyl moiety. Examples of “-(C ₁ -C ₈ ) -alkyl” or “-(C ₁ -C ₈ ) -alkylene” include 1, 2, 3, 4, 5, 6, 7 carbon atoms Alkyl residues containing 8 or 8, methyl, methylene, ethyl, ethylene, propyl, propylene, butyl, butylene, pentyl, pentylene, hexyl, heptyl or octyl, n-isomers of all these residues, isopropyl, Isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, secondary-butyl, tBu, tert-pentyl, secondary-butyl , Tert-butyl or tert-pentyl.

Unsaturated alkyl residues are, for example, vinyl, 1-propenyl, 2-propenyl (= allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2- Alkenyl residues such as butenyl, 5-hexenyl or 1,3-pentadienyl, or alkynyl residues such as ethynyl, 1-propynyl, 2-propynyl (= propargyl) or 2-butynyl .

The term "-(C ₃ -C ₈ ) -cycloalkyl" refers to three, four, five, six, seven, or eight members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl It is understood as a cycloalkyl moiety containing an original carbocyclic ring, which may also be substituted and / or unsaturated. For example, unsaturated cyclic alkyl groups such as cyclopentenyl or cyclohexenyl and unsaturated cycloalkyl groups can be linked through any carbon atom.

The term "alkyl sulfonate" is understood as an alkyl moiety containing one, two, three, four, five or six carbon atoms substituted by a sulfonate. Examples of such moieties are methylsulfonate (mesylate), ethylsulfonate, propylsulfonate, butylsulfonate, pentylsulfonate or hexylsulfonate.

The term "A1, A2, A3 and A4 are independently selected from carbon atoms or nitrogen atoms, and together with the two carbon atoms in formula (I) form a stable aromatic or heteroaromatic ring", for example, benzene, pyrazine And a residue selected from pyridazine, pyridine, pyrimidine, triazine or tetraazine.

The term "-(C ₆ -C ₁₄ ) -aryl" is understood to mean an aromatic hydrocarbon radical containing 6 to 14 carbon atoms in the ring. Examples of-(C ₆ -C ₁₄ ) -aryl radicals include phenyl, naphthyl (eg 1-naphthyl and 2-naphthyl), biphenylyl (eg 2-biphenylyl, 3-biphenylyl and 4-biphenylyl), anthryl or fluorenyl. Biphenylyl radicals, naphthyl radicals and especially phenyl radicals are preferred aryl radicals.

The term "aryl sulfonate" is understood as aryl as defined above substituted by sulfonate. Examples of such compounds are benzenesulfonates, tosylate, nitrobenzenesulfonates or bromobenzenesulfonates.

The term “-(C ₅ -C ₁₄ ) -heteroaryl” refers to a monocyclic, dicyclic or tricyclic system in which one or more of 5 to 14 carbon reductions are replaced by heteroatoms such as nitrogen, oxygen or sulfur. For example, acridinyl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofura Neil, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-carbazolyl, Carbolinyl, Chromyl, Chromyl, Shin Nolinyl, decahydrocinolinyl, 4,5-dioxydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo [1,3,4] oxathiazinyl, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, Imidazolinyl, imidazolyl, indanyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isoindazolyl, isoindolinyl, Isoindole Reel, isoquinolinyl, isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopipiperazinyl, morpholinyl , Naphthyridinyl, octahydroisoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2-oxa-thipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepinyl, 1,2-oxazinyl, 1,3 Oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxinyl Noxazinyl, phthalazinyl, piperazinyl, piperidinyl, putridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrazolo [3,4-b] pyridine, Pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridotia Reel, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl , Quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl , Thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl , Thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4- Triazinyl, 1,3,5-t Liazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthate Neal.

The term "three to seven membered cyclic moieties containing one, two, three or four heteroatoms" refers to azepine, azetidine, aziridine, azirin, 1,4-diazephan, 1,2 Diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dioxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan , Imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopi Perazine, morpholine, 1,2-oxa-thiphan, 1,2-oxathiolane, 1,4-oxazepan, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, Oxazole, oxaziridine, oxetane, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroli Dinon, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyri Dean, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine , Thiazoline, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3- It refers to the structure of a heterocycle selected from compounds such as triazoles or 1,2,4-triazoles.

The term “R 1 and R 2, R 2 and R 3, or R 3 and R 4 together with the atoms to which they are attached contain 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen Forms a 5- or 8-membered ring "azepine, azirin, azocan, azocan-2-one, cycloheptyl, cyclohexyl, cyclooctane, cyclooctene, 1,4-diazepane, 1,2- Diazepine, 1,3-diazepine, 1,4-diazepine, [1,2] diazokane-3-one, [1,3] diazokane-2-one, [1,4] diazokane, dioxane Photo, dioxazole, [1,4] dioxocan, 1,3-dioxolane, dioxol, 1,3-dioxolene, furan, imidazole, imidazolidine, imidazoline, isothiazole, Isothiazolidine, isothiazoline, isothiazole, isoxazole, isoxazolidine, isoxazolin, 2-isoxazolin, ketomorpholine, ketopiperazin, morpholine, 1,2-oxa-thier Board, 1,2-oxathiolane, 1,4-oxazepan, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxaziridine, [1, 4] oxazocan, [1,3] oxazocan-2-one, oxocan, oxocan-2-one, oxazole, piperidine, piperazine, phenyl, pyridazine, pyridine, pyrimidine, pyran, pyrazine , Pyrazole, pyrazolepyrrole, pyrazolidine, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, 5,6,7,8-tetrahydro-1H-a Joshin-2-one, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine, thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4- Thiazine, thiazole, 1,3-thiazole, thiazolidine, thiazolin, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine And residues selected from compounds such as 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole.

The term _{"- (C 1 -C 3)} - alkyl, fluoroalkyl" is a partially or fully fluorinated alkyl-residue, and which _{-CF 3, -CHF 2, -CH 2} F, -CHF-CF 3, -CHF-CHF 2 , -CHF-CH ₂ F, -CH ₂ -CF ₃ , -CH ₂ -CHF ₂ , -CH ₂ -CH ₂ F, -CF ₂ -CF ₃ , -CF ₂ -CHF ₂ , -CF ₂ -CH ₂ F, -CH ₂ -CHF-CF ₃ , -CH ₂ -CHF-CHF ₂ , -CH ₂ -CHF-CH ₂ F, -CH ₂ -CH ₂ -CF ₃ , -CH ₂ -CH ₂ -CHF ₂ , -CH ₂ -CH ₂ -CH ₂ F, -CH ₂ -CF ₂ -CF ₃ , -CH ₂ -CF ₂ -CHF ₂ , -CH ₂ -CF ₂ -CH ₂ F, -CHF-CHF-CF ₃ , -CHF-CHF-CHF ₂ , -CHF-CHF-CH ₂ F, -CHF-CH ₂ -CF ₃ , -CHF-CH ₂ -CHF ₂ , -CHF-CH ₂ -CH ₂ F, -CHF-CF ₂ -CF ₃ , -CHF-CF ₂ -CHF ₂ , -CHF-CF ₂ -CH ₂ F, -CF ₂ -CHF-CF ₃ , -CF ₂ -CHF-CHF ₂ , -CF ₂ -CHF-CH ₂ F , -CF ₂ -CH ₂ -CF ₃ , -CF ₂ -CH ₂ -CHF ₂ , -CF ₂ -CH ₂ -CH ₂ F, -CF ₂ -CF ₂ -CF ₃ , -CF ₂ -CF ₂ -CHF ₂ or And residues such as -CF ₂ -CF ₂ -CH ₂ F.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.

The term "triplate" refers to trifluoro-methanesulfonic acid ester or trifluoromethanesulfonate.

The term "nonaplate" refers to 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonic acid ester or 1,1,2,2,3,3,4,4 , 4-nonafluoro-1-butanesulfonate.

The term "at least one of R1, R2, R3 or R4 is absent when at least one of A1, A2, A3 or A4 is a nitrogen atom" refers to a moiety wherein said nitrogen atom is not replaced by any moiety. The residue pyridine is formed when A 1 is a nitrogen atom, A 2, A 3 and A 4 are each carbon atoms and R 4 is absent and R 1, R 2 and R 3 are each hydrogen atoms. If R1, R2 and R3 are each not hydrogen atoms but one of the residues is specified b) to x), then a substituted pyridine residue is formed. When A1 and A2 are each nitrogen atoms, A3 and A4 are each carbon atoms, R4 and R3 are absent and R1 and R2 are each hydrogen atoms, the residue pyridazine is formed. When R1 and R2 are each hydrogen atoms but one of the residues is specified b) to x), a substituted pyridazine residue is formed.

Optically active carbon atoms present in compounds of formula (I) may have an R or S configuration independently of one another. The compounds of formula (I) may exist in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and / or diastereomers, for example racemic forms. The present invention relates to pure diastereomers and diastereomeric mixtures as well as pure enantiomeric and enantiomeric mixtures. The present invention includes mixtures of two or more stereoisomers of formula (I), which include all ratios of stereoisomers in the mixture. If the compounds of formula (I) can exist as E isomers or Z isomers (or cis isomers or trans isomers), the invention relates to pure E isomers and pure Z isomers as well as to all proportions of E / Z mixtures. The invention also includes all tautomeric forms of the compounds of formula (I).

Diastereomers comprising E / Z isomers can be separated into individual isomers, for example, by chromatography. The racemates are separated by conventional methods, for example by chromatography on chiral or by resolution, for example by recrystallization of diastereomeric salts obtained with optically active acids or bases. Can be separated into two enantiomers. Stereochemically uniform compounds of formula (I) can also be obtained using stereochemically uniform starting materials or using stereoselective reactions.

 Starting materials or building blocks for use in general synthetic procedures that can be applied to the preparation of compounds of formula (I) are readily available to those skilled in the art. In many cases they are commercially available or described in the literature. Alternatively, they can be prepared from readily available precursor compounds similar to the processes described in the literature or similar to the processes described herein.

Further, in order to obtain the desired substituents in the benzene nucleus and in the heterocyclic nucleus of the 2H-indazole or 2H-azinazole ring system in the formula (I), The functional groups introduced into the ring system can be chemically modified.

In particular, the groups present in the 2H-indazole or 2H-azinazole ring system can be modified by various reactions, so that the desired residues R0, R1, R2, R3, R4 and R5 are obtained. For example, ester groups present in the benzene nucleus can be hydrolyzed to the corresponding carboxylic acid, which can be activated and then reacted with an amine or alcohol under standard conditions. Ether groups present in the benzene nucleus, such as benzyloxy groups or other readily degradable ether groups, can be decomposed to provide hydroxyl groups, which are then combined with various agents, for example etherification agents or activators. By reaction, the hydroxyl group can be replaced by other group. Sulfur containing groups can react similarly.

Due to the fact that in the case of the present invention the functional group is attached to the 2H-indazole or 2H-azidadazole ring, in certain cases the reaction conditions may be specifically adapted or the specific reagents may be selected from a variety of reagents that may be used in the conversion reaction, or Or it may be necessary to take specific steps to achieve the desired conversion, for example using protection group techniques. In this case, however, finding suitable reaction variants and reaction conditions is not a problem for the skilled person at all.

In the preparation of the compound of formula (I), a protecting group suitable for synthesis problems or introducing functional groups in the form of precursor groups which will subsequently be converted to the desired functional groups or reducing functional groups which reduce or prevent undesirable reactions or side reactions in each synthesis step Temporary blocking by a strategy is usually advantageous or necessary. Such strategies are well known to those skilled in the art. As an example of the precursor group, cyan groups may be mentioned, which may be modified in subsequent steps into carboxylic acid derivatives or by reduction to aminomethyl groups. A protecting group can have the meaning of a solid phase, and decomposition from the solid phase means removal of the protecting group. The use of such techniques is known to those skilled in the art. For example, a phenolic hydroxy group can be attached to the trityl-polystyrene resin, which acts as a protecting group, and the molecule is removed from the resin by trifluoroacetic acid (TFA) treatment at subsequent stages of the synthesis. Decompose

It may be advantageous or even necessary in many cases to benefit from electromagnetic waves to accelerate or accelerate or facilitate the reaction in the synthesis process. Some reactions are described, for example, in M. Larhed, A. Hallberg, Drug Discovery Today, 8 (2001) 406.

Physiologically acceptable salts of compounds of formula I are physiologically acceptable nontoxic salts, in particular pharmaceutically useful salts. Salts of compounds of formula (I) containing acidic groups such as carboxyl groups (COOH) are, for example, alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, as well as Salts with physiologically acceptable quaternary ammonium ions such as tetramethylammonium or tetraethylammonium, and ammonia and physiologically acceptable organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, Acid addition salts with triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine). Basic groups contained in compounds of formula (I), for example amino groups or guanidino groups, can be, for example, inorganic acids (eg hydrochloric acid, bromic acid, sulfuric acid, nitric acid or phosphoric acid) or organic carboxylic acids and sulfonic acids (eg : Acid addition salt with formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid). Compounds of formula (I) containing both basic and acidic groups such as guanidino and carboxyl groups may also exist as zwitterions (betaines), which are also within the scope of the invention.

Salts of compounds of formula (I) can be obtained by conventional methods known to those skilled in the art, for example by combining the compounds of formula (I) with inorganic acids, organic acids, inorganic bases or organic bases in solvents or dispersants or from cation from other salts. It can be obtained by exchange or anion exchange. The present invention also encompasses all salts of the compounds of formula (I), and due to their low physiological tolerances it is not suitable for use directly in pharmaceuticals, but for example intermediates for carrying out further chemical modification of the compounds of formula (I) As starting materials for preparing the physiologically acceptable salts.

Further embodiments of the present invention provide a pharmaceutical, diagnostic agent, liquid crystal, polymer, herbicide, fungicide, nematicide, insecticide, insecticide, acaricide and pesticide according to the present invention. Use of a compound of formula (I) prepared by the process.

Preferred methods include, but are not limited to, those described in the Examples. In addition, the compounds of formula (I) can be used as synthetic intermediates for the preparation of other compounds, in particular other pharmaceutically active ingredients, which are to be obtained from the compounds of formula (I), for example by introduction of substituents or modification of functional groups. Can be.

General synthetic sequences for preparing compounds useful in the present invention are outlined in the following examples. The description of the various aspects of the present invention as well as the practical procedures therefor have been described where appropriate. The following examples are merely to illustrate the invention, but are not intended to limit the scope or gist thereof. Those skilled in the art will readily understand that known variations of the conditions and methods described in the examples can be used to synthesize the compounds of the present invention.

If an acid such as trifluoroacetic acid or acetic acid is used in the final step of the synthesis of the compound, for example trifluoroacetic acid is used to remove the tBu group or if the compound is in some cases a post-treatment process, for example When purified by chromatography using eluents containing these acids according to the details of the freeze-drying process, the compounds are partially or completely, in the form of salts of the acids used, for example acetate or Obtained in the form of trifluoroacetic acid salt or hydrochloride.

Abbreviations used:

Tert-butyl tBu

Dibenzylideneacetone dba

N, N-dimethylformamide DMF

Ethyl acetate EtOAc

N-methylpyrrolidone NMP

High Speed Atomic Bomb Act

Liquid Chromatography LC-MS with Mass Spectrometer

Room temperature 21-24 ° C RT

Trifluoroacetic acid TFA

General procedure for forming a one-pot of 2H-indazole from 2-haloacetylene and monosubstituted hydrazine: Add Pd source, ligand, solvent and base to an oven dried reaction tube with magnetic stir bar . The reaction tube was sealed with a septum and stirred for 30 minutes at room temperature under an inert atmosphere (nitrogen or argon) before adding reagents. The reagent was added, the mixture was heated to the desired temperature and the reaction run was carried out by LCMS. At the end of the reaction as judged by LCMS, the reaction mixture was cooled to room temperature, quenched with brine and extracted with EtOAc. The organic phase was dried over Na ₂ SO _{4 and} then filtered or filtered through Varian cartridge Chem Elut 12198007, then the solvent was removed by rotary evaporation and the residue was CH ₂ Cl Purification by FC on silica using ₂ / EtOAc or in some cases CH ₂ Cl ₂ / MeOH. After rotary evaporation of the organic solvent, the desired 2H-indazole was obtained with high purity.

Example 1 3-benzyl-2-phenyl-2H-indazole

According to the general procedure outlined above, 4.4 mg of PdCl ₂ (5 mol%), 14.5 mg of tBu ₃ PHBF ₄ (10 mol%), 228.1 mg of Cs ₂ CO ₃ (1.4 equiv) and 2.5 mL of DMF were added to the reaction tube. Loaded. After stirring for 30 minutes at room temperature under argon flow, 1-chloro-2-phenylethynyl-benzene (106.3 mg, 1.0 equiv) and phenylhydrazine (75.7 mg, 1.4 equiv) were added and the reaction was added for 3 hours. Heated to 130 ° C. After cooling to rt, the reaction mixture was quenched with brine (30 mL) and extracted with EtOAc (2 × 30 mL) and the organic phase was dried by eluting through Varian Chem Elut 12198007 cartridge. Removal of the solvent gave crude indazole as dark brown oil, which was purified by FC on silica using CH ₂ Cl ₂ / EtOAc to give 115.0 mg (81%) of 3-benzyl-2-phenyl-2H-. An indazole colorless oil is obtained, which solidifies upon standing.

HRMS (FAB): calcd for C ₂₀ H ₁₇ N ₂ (M + H ⁺ ) 285.1391 found 285.1385.

Example 2:

The reaction was carried out according to Example 1 using 1-bromo-2-phenylethynyl-benzene (128.6 mg, 1.0 equiv) instead of 1-chloro-2-phenylethynyl-benzene. The reaction gave 112.2 mg (79%) of 3-benzyl-2-phenyl-2H-indazole.

Example 3:

The reaction was carried out for 20 hours at a reaction temperature of 110 ° C. using 8.9 mg of PdCl ₂ (10 mol%), 29.0 mg of tBu ₃ PHBF ₄ (20 mol%) and 244.4 mg Cs ₂ CO ₃ (1.5 equiv). It was performed according to. The reaction gave 106.5 mg (75%) of 3-benzyl-2-phenyl-2H-indazole.

Example 4:

The reaction was carried out according to Example 1 using 1.8 mg of PdCl ₂ (2 mol%) and 2.9 mg of tBu ₃ PHBF ₄ (4 mol%). The reaction gave 105.1 mg (74%) of 3-benzyl-2-phenyl-2H-indazole.

Example 5:

The reaction was carried out according to Example 1 using 179.2 mg of Cs ₂ CO ₃ (1.1 equiv). The reaction gave 100.8 mg (71%) of 3-benzyl-2-phenyl-2H-indazole.

Example 6:

The reaction was carried out at 20 ° C. at 110 ° C. using 22.9 mg Pd ₂ (dba) ₃ (5 mol%), 29.0 mg tBu ₃ PHBF ₄ (20 mol%) and 244.4 mg Cs ₂ CO ₃ (1.5 equiv). It was carried out according to example 1 for a time. The reaction provided 105.1 mg (74%) of 3-benzyl-2-phenyl-2H-indazole.

Example 7:

The reaction was carried out in accordance with Example 6 using dimethylacetamide (2.5 mL) as solvent. The reaction gave 102.2 mg (72%) of 3-benzyl-2-phenyl-2H-indazole.

Example 8:

The reaction was carried out in accordance with Example 6 using N-methylpyrrolidone (NMP, 2.5 mL) as solvent. The reaction gave 108.0 mg (76%) of 3-benzyl-2-phenyl-2H-indazole.

Example 9:

The reaction was carried out according to Example 8 for 4 hours at a reaction temperature of 130 ° C. The reaction gave 109.3 mg (77%) of 3-benzyl-2-phenyl-2H-indazole.

Example 10:

The reaction was carried out according to Example 1 using 101.2 mg of phenylhydrazine hydrochloride (1.4 equiv) and 438.8 mg Cs ₂ CO ₃ (2.7 equiv). The reaction gave 109.3 mg (77%) of 3-benzyl-2-phenyl-2H-indazole.

Example 11 2-phenyl-3-pyridin-2-ylmethyl-2H-indazole

The reaction was carried out according to Example 1 using 106.8 mg of 2- (2-chloro-phenylethynyl) -pyridine for 3 hours at a reaction temperature of 110 ° C. This gave 128.4 mg (90%) of the title compound.

HRMS (FAB): Calcd for C ₁₉ H ₁₆ N ₃ (M + H ⁺ ) 286.1344, found 286.1337.

Example 12: 2-phenyl-3- (4-trifluoromethyl-benzyl) -2H-indazole

The reaction was carried out according to Example 1 for 3 hours at a reaction temperature of 110 ° C. using 140.3 mg of 1-chloro-2- (4-trifluoromethylphenyl) ethynyl-benzene. This gave 123.8 mg (83%) of the title compound.

Example 13: 2-phenyl-3- (4-methoxy-benzyl) -2H-indazole

The reaction was carried out according to Example 1 for 3 hours at a reaction temperature of 110 ° C. using 121.3 mg of 1-chloro-2- (4-methoxyphenyl) ethynyl-benzene. This gave 135.2 mg (86%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₉ N ₂ 0 (M + H ⁺ ) 315.1497, found 315.1491.

Example 14 3- (6-methoxy-naphthalen-2-ylmethyl) -2-phenyl-2H-indazole

The reaction was carried out according to Example 1 for 6 hours at a reaction temperature of 110 ° C. using 146.4 mg 2- (2-chloro-phenylethynyl) -6-methoxy-naphthalene. This gave 127.6 mg (70%) of the title compound.

HRMS (FAB): Calcd for C ₂₅ H ₂₁ N ₂ 0 (M + H ⁺ ) 365.1654. Found 365.1648.

Example 15 N, N-diisopropyl-2- (2-phenyl-2H-indazol-3-yl) -acetamide

The reaction was carried out according to Example 1 for 2 hours at a reaction temperature of 110 ° C. using 131.9 mg of 3- (2-chloro-phenyl) -propanoic acid diisopropylamide. This gave 105.5 mg (63%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₂₆ N ₃ 0 (M + H ⁺ ) 336.2075, found 336.2068.

Example 16: (2-phenyl-2H-indazol-3-yl) -acetic acid tert-butyl ester

The reaction was carried out according to Example 1 for 2 hours at a temperature of 110 ° C. using 118.4 mg of (2-chloro-phenyl) -propionic acid tert-butyl ester. This gave 143.4 mg (93%) of the title compound.

HRMS (FAB): Calcd for C ₁₉ H ₂₁ N ₂ 0 ₂ (M + H ⁺ ) 309.1603. Found 309.1596.

Example 17: 3- (2,2-diethoxy-ethyl) -2-phenyl-2H-indazole

The reaction was carried out according to Example 1 using 119.4 mg of 1-chloro-2- (3,3-diethoxy-prop-1-ynyl) -benzene. The reaction mixture was worked up by filtration through a short silica plug to remove the base and catalyst using iPr ₂ O and then the solvent was evaporated. The crude product was purified by FC on silica gel using CH ₂ Cl ₂ / EtOAc. This gave 85.4 mg (55%) of the title compound.

HRMS (FAB): Calcd for C ₁₉ H ₂₃ N ₂ 0 ₂ (M + H ⁺ ) 311.1760, found 311.1754.

Example 18 3- (2,2-dimethyl-propyl) -2-phenyl-2H-indazole

The reaction was carried out in accordance with Example 1 using 96.4 mg of 1-chloro-2- (3,3-dimethyl-but-1-ynyl) -benzene for a reaction time of 20 hours. This gave 11.9 mg (9%) of the title compound.

Example 19: 3-hexyl-2-phenyl-2H-indazole

The reaction was carried out in accordance with Example 1 using 103.4 mg of 1-chloro-2-hept-1-ynyl-benzene for a reaction time of 20 hours. This gave 15.3 mg (11%) of the title compound.

Example 20 3-cyclopropylmethyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester

The reaction was carried out in accordance with Example 1 using 138.4 mg of 3-chloro-4-cyclopropylethynyl-benzoic acid tert-butyl ester for a reaction time of 4 hours. This gave 81.9 mg (47%) of the title compound.

Example 21 3-benzyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester

The reaction was carried out according to Example 1 using 156.4 mg of 3-chloro-4-phenylethynyl-benzoic acid tert-butyl ester. This gave 133.1 mg (69%) of the title compound.

HRMS (FAB): calcd for C ₂₅ H ₂₅ N ₂ 0 ₂ (M + H ⁺ ) 385.1916. Found 385.1911.

Example 22 3-cyclopentylmethyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester

The reaction was carried out according to Example 1 for 4 hours using 152.4 mg of 3-chloro-4-cyclopentylethynyl-benzoic acid tert-butyl ester. This gave 17.3 mg (9%) of the title compound.

HRMS (FAB): calcd for C ₂₄ H ₂₈ N ₂ 0 ₂ Na (M + Na ⁺ ) 399.2048. Found 399.2045.

Example 23: Diethyl- [2- (2-phenyl-2H-indazol-3-yl) -ethyl] -amine

The reaction was carried out according to Example 1 using a reaction time of 20 hours using 110.9 mg of [3- (2-chloro-phenyl) -prop-2-ynyl] -diethyl-amine. This gave 44.0 mg (30%) of the title compound.

HRMS (FAB): calcd for C ₁₉ H ₂₄ N ₃ (M + H ⁺ ) 294.1970, found 294.1964.

Example 24: 2-phenyl-3- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-indazole

The reaction was carried out according to Example 1 at 100 ° C. for 2 hours using 125.4 mg of 2- [3- (2-chloro-phenyl) -prop-2-ynyloxy] -tetrahydro-pyran. This gave 37.1 mg (23%) of the title compound.

Example 25 3-benzyl-2-phenyl-5-trifluoromethyl-2H-indazole

The reaction was carried out according to example 1 using 140.3 mg of 1-chloro-2-phenylethynyl-4-trifluoromethyl-benzene at 110 ° C. for a reaction time of 20 hours. This gave 107.5 mg (61%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₆ N ₂ F ₃ (M + H ⁺ ) 353.1266. Found 353.1261.

Example 26 3-benzyl-6-fluoro-2-phenyl-2H-indazole

The reaction was carried out according to Example 1 using 115.3 mg of 2-chloro-4-fluoro-1-phenylethynyl-benzene at 20 ° C. for a reaction time of 20 hours. This gave 64.4 mg (43%) of the title compound.

HRMS (FAB): calcd for C ₂₀ H ₁₆ N ₂ F (M + H ⁺ ) 303.1297, found 303.1292.

Example 27 3-benzyl-4-methyl-2-phenyl-2H-indazole

The reaction was carried out according to Example 1 using 113.4 mg of 1-chloro-3-methyl-2-phenylethynyl-benzene at 110 ° C. for a reaction time of 4 hours. This gave 95.8 mg (64%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₉ N ₂ (M + H ⁺ ) 299.1548. Found 299.1543.

Example 28 3-benzyl-6-methoxy-2-phenyl-2H-indazole

The reaction was carried out according to Example 1 using 121.4 mg of 2-chloro-4-methoxy-1-phenylethynyl-benzene at 130 ° C. for a reaction time of 4 hours. This gave 114.5 mg (73%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₉ N ₂ 0 (M + H ⁺ ) 315.1497, found 315.1491.

Example 29: 3-benzyl-5-methoxy-2-phenyl-2H-indazole

The reaction was carried out in accordance with Example 1 using 121.4 mg of 1-chloro-4-methoxy-2-phenylethynyl-benzene at 110 ° C. for a reaction time of 5 hours. This gave 98.7 mg (63%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₉ N ₂ 0 (M + H ⁺ ) 315.1497, found 315.1491.

Example 30 Toluene-4-sulfonic acid 3-benzyl-2-phenyl-2H-indazol-6-yl ester

The reaction was carried out in accordance with Example 1 using 191.4 mg of toluene-4-sulfonic acid 3-chloro-4-phenylethynyl-phenyl ester at 110 ° C. for a reaction time of 4 hours. This gave 80.7 mg (36%) of the title compound.

HRMS (FAB): Calcd for C ₂₇ H ₂₃ N ₂ 0 ₃ S (M + H ⁺ ) 455.1429. Found 455.1429.

Example 31 3-benzyl-2-phenyl-2H-indazole-5-carboxylic acid

The reaction was carried out according to Example 1 using 128.3 mg of 4-chloro-3-phenylethynyl-benzoic acid at 110 ° C. for a reaction time of 4 hours. The reaction was purified by preparative RP HPLC using MeCN / H ₂ O / TFA as eluent. This gave 75.6 mg (46%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₇ N ₂ 0 ₂ (M + H ⁺ ) 329.1290, found 329.1286.

Example 32: 3-benzyl-2-phenyl-2H-pyrazolo [4,3-c] pyridine

The reaction was carried out in accordance with Example 1 using 156.4 mg of 4-chloro-3-phenylethynyl-pyridine at 110 ° C. for a reaction time of 3 hours. This gave 24.0 mg (17%) of the title compound.

Example 33: 3-benzyl-2- (4-methoxy-phenyl) -2H-indazole

The reaction was carried out according to Example 1 using 122.2 mg of 4-methoxyphenylhydrazine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv) at 130 ° C. for a reaction time of 4 hours. This gave 125.0 mg (80%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₉ N ₂ 0 (M + H ⁺ ) 315.1497, found 315.1491.

Example 34 3-benzyl-2- (4-fluoro-phenyl) -2H-indazole

The reaction was carried out in accordance with Example 1 using 113.8 mg of 4-fluorophenylhydrazine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv) at 130 ° C. for a reaction time of 3 hours. This gave 128.8 mg (85%) of the title compound.

HRMS (FAB): calcd for C ₂₀ H ₁₆ N ₂ F (M + H ⁺ ) 303.1297, found 303.1292.

Example 35 3-benzyl-2- (2-fluoro-phenyl) -2H-indazole

The reaction was carried out according to Example 1 using 113.8 mg of 2-fluorophenyl-hydrazine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv) at 130 ° C. for a reaction time of 5 hours. This gave 123.0 mg (81%) of the title compound.

HRMS (FAB): calcd for C ₂₀ H ₁₆ N ₂ F (M + H ⁺ ) 303.1297, found 303.1292.

Example 36 4- (3-benzyl-indazol-2-yl) -benzonitrile

The reaction was carried out according to Example 1 using 118.7 mg 4-cyanophenylhydrazine hydrochloride and 439.9 mg Cs ₂ CO ₃ (2.7 equiv) at 130 ° C. for a reaction time of 3 hours. This gave 143.3 mg (93%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₁₆ N ₃ (M + H ⁺ ) 310.1344, found 310.1340.

Example 37 3-benzyl-2-naphthalen-1-yl-2H-indazole

The reaction was carried out according to Example 1 for 4 hours at 130 ° C. using 118.7 mg of 1-naphthylhydrazine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv). This gave 105.7 mg (63%) of the title compound.

HRMS (FAB): Calcd for C ₂₄ H ₁₉ N ₂ (M + H ⁺ ) 335.1548, found 335.1548.

Example 38 3-benzyl-2-pyridin-4-yl-2H-indazole

The reaction was carried out according to Example 1 using 101.9 mg 4-hydrazino-pyridine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv) at 130 ° C. for a reaction time of 3 hours. This gave 134.6 mg (94%) of the title compound.

HRMS (FAB): Calcd for C ₁₉ H ₁₆ N ₃ (M + H ⁺ ) 286.1344, found 286.1339.

Example 39: 4- (3-benzyl-indazol-2-yl) -quinoline

The reaction was carried out in accordance with Example 1 using 137.0 mg 4-hydrazinoquinoline hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv) at 130 ° C. for a reaction time of 3 hours. This gave 74.9 mg (45%) of the title compound.

Example 40 3-benzyl-2-pyridin-4-yl-2H-indazol-6-carboxylic acid tert-butyl ester

The reaction was carried out with 156.4 mg of 3-chloro-4-phenylethynyl-benzoic acid tert-butyl ester, 101.9 mg of 4-hydrazinopyridine hydrochloride (1.4 equiv) and 456.2 mg of Cs ₂ CO ₃ (2.8 equiv) Was carried out according to Example 1 at 110 ° C. for a reaction time of 2 hours. This gave 104.7 mg (54%) of the title compound.

Calcd for C ₂₄ H ₂₄ N ₃ 0 ₂ (M + H ⁺ ) 386.1869, found 386.1864.

Example 41 3-cyclopropylmethyl-2-pyridin-4-yl-2H-indazol-6-carboxylic acid tert-butyl ester

The reaction was carried out with 138.4 mg of 3-chloro-4-cyclopropylethynyl-benzoic acid tert-butyl ester, 101.9 mg 4-hydrazinopyridine hydrochloride (1.4 equiv) and 456.2 mg Cs ₂ CO ₃ (2.8 equiv) Was used according to Example 1 at 110 ° C. for a reaction time of 4 hours. This gave 73.0 mg (42%) of the title compound.

HRMS (FAB): calcd for C ₂₁ H ₂₄ N ₃ O ₂ (M + H ⁺ ) 350.1869, found 350.1864.

Example 42: 3-benzyl-2-methyl-2H-indazole

The reaction was carried out according to Example 1 using 32.3 mg of methylhydrazine at 110 ° C. for a reaction time of 5 hours. This gave 68.6 mg (62%) of the title compound.

HRMS (FAB): calcd for C ₁₅ H ₁₅ N ₂ (M + H ⁺ ) 223.1235. Found 223.1231.

Example 43: 3-benzyl-2-phenethyl-2H-indazole

The reaction was carried out in accordance with Example 1 using 95.3 mg of phenethylhydrazine at 110 ° C. for a reaction time of 20 hours. This gave 77.7 mg (50%) of the title compound.

HRMS (FAB): calcd for C ₂₂ H ₂₁ N ₂ (M + H ⁺ ) 313.1705, found 313.1698.

Example 44 3-benzyl-2-isopropyl-2H-indazole

The reaction was carried out according to Example 1 using 77.4 mg of isopropylhydrazine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equivalents) at 110 ° C. for a reaction time of 20 hours. This gave 68.4 mg (55%) of the title compound.

HRMS (FAB): Calcd for C ₁₇ H ₁₉ N ₂ (M + H ⁺ ) 251.1548, found 251.1542.

Example 45 3-benzyl-2-cyclohexyl-2H-indazole

The reaction was carried out according to Example 1 using 105.5 mg of cyclohexyl-hydrazine hydrochloride and 439.9 mg of Cs ₂ CO ₃ (2.7 equiv) at a reaction time of 110 hours at 110 ° C. This gave 69.4 mg (48%) of the title compound.

HRMS (FAB): calcd for C ₂₀ H ₂₃ N ₂ (M + H ⁺ ) 291.1861, found 291.1856.

Example 46 3-benzyl-2-thiophen-2-ylmethyl-2H-indazol-6-carboxylic acid tert-butyl ester

The reaction was carried out at 156.4 mg of 3-chloro-4-phenylethynyl-benzoic acid tert-butyl ester, 164.7 mg thiophen-2-ylmethyl-hydrazine hydrochloride (2.0 equiv) and 488.7 mg Cs ₂ CO ₃ (3.0 equiv ) Was carried out according to Example 1 at 110 ° C. for a reaction time of 5 hours. This gave 72.8 mg (36%) of the title compound.

Claims (11)

Reacting a compound of formula (II) with a compound of formula (III) or any salt thereof in the presence of a transition metal catalyst to obtain a compound of formula (I) and optionally converting the compound of formula (I) to its physiologically acceptable salt A process for preparing a physiologically acceptable salt of a compound of formula (I) and / or a mixture of all stereoisomeric forms and / or all proportions of these forms and / or compounds of formula (I), comprising. Formula I

Formula II

Formula III

In the above formulas (I), (II) and (III), A1, A2, A3 and A4 are each independently selected from a carbon atom or a nitrogen atom, and together with two carbon atoms in the formula (I) form a stable aromatic or heteroaromatic ring, Q is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; -(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13; - (C ₁ -C ₄₎ - alkylene -O- (C ₁ -C ₄₎ - alkylene; - (C ₁ -C ₄₎ - alkylene -O-; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, and J is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; -(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, and R0, R1, R2, R3 and R4 are the same or different independently of each other, a) hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted 1 to 3 times by R 13, c) halogen, d) phenyloxy-, wherein said phenyloxy is unsubstituted or substituted one to three times by R13; _{e) - (C 1 -C 3} ) - alkyl, fluoroalkyl, f) -N (R 10)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13, g)-(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, h) — (C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di-, tri-, or tetra-substituted independently of one another by R 13, i)-(C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, j) 3- to 7-membered cyclic moieties containing one, two, three or four heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other by R13. Mono-, di-, tri- or tetra-substituted), k) -O-CF ₃ , l) —O— (C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13; m) -NO ₂ , n) -CN, o) -OH, p) -C (O) -R10, q) -C (O) -O-R11, r) -C (O) -N (R11) -R12, s) -N (R11) -R12, t) -N (R10) -SO ₂ -R10, u) -S-R10, v) -SO _n -R 10, where n is 1 or 2, w) -SO ₂ -N (R11) -R12 or x) -O-SO ₂ -R13 y) at least one of R1, R2, R3 or R4 is absent when at least one of A1, A2, A3 or A4 is a nitrogen atom, or A 5 member containing 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen together with the atoms to which R1 and R2, R2 and R3 or R3 and R4 are attached Or an 8-membered ring, wherein said ring is unsubstituted or mono-, di-, tri- or tetra-substituted by R 14, and R5 is a)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13, b) halogen, c) phenyloxy-, wherein said phenyloxy is unsubstituted or substituted one to three times by R13; _{d) - (C 1 -C 3} ) - alkyl, fluoroalkyl, e) -N (R10) - ( C 1 -C 4) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13), f)-(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, g)-(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, h) — (C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, i) 3- to 7-membered cyclic moieties containing one, two, three or four heteroatoms selected from nitrogen, sulfur or oxygen, wherein the cyclic moieties are unsubstituted or independently of each other by R13 Mono-, di-, tri- or tetra-substituted), j) -O-CF ₃ , _{k) -O- (C 1 -C 4} ) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13), l) -NO ₂ , m) -CN, n) -OH, o) -C (O) -R10, p) -C (O) -O-R11, q) -C (O) -N (R11) -R12, r) -N (R11) -R12, s) -N (R10) -SO ₂ -R10, t) -S-R10, u) -SO _n -R 10, where n is 1 or 2, v) -SO ₂ -N (R11) -R12 or w) -O-SO ₂ -R13, R 10 is a hydrogen atom, — (C ₁ -C ₃ ) -fluoroalkyl or — (C ₁ -C ₆ ) -alkyl, R11 and R12 are the same or different independently from each other, a) hydrogen atom, b)-(C ₁ -C ₆ ) -alkyl, wherein said alkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13, c)-(C ₆ -C ₁₄ ) -aryl-, wherein the aryl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13; or d)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13, and R 13 is halogen, —NO ₂ , —CN, ═O, —OH, — (C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, -CF ₃ , phenyloxy-, -C ( O) -R10, -C (O) -O-R17, -C (O) -N (R17) -R18, -N (R17) -R18, -N (R10) -SO ₂ -R10, -S- R 10, -SO _n -R 10, wherein n is 1 or 2, -SO ₂ -N (R 17) -R 18,-(C ₆ -C ₁₄ ) -aryl, wherein the aryl is unsubstituted or substituted for R 14 Mono-, di-, or tri-substituted independently from each other),-(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is unsubstituted or mono-, di-, or trisubstituted independently of one another by R14 ,-(C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14, or a heteroatom selected from nitrogen, sulfur or oxygen 1 Three to seven membered cyclic moieties containing dogs, two, three or four, wherein the cyclic moieties are unsubstituted or poisoned with each other by R14 Typically one is substituted, disubstituted or tri-substituted), R14 is halogen, -OH, = O, -CN, -CF ₃ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -NO ₂ , -C (O) -OH , -N (R11) -R12, -C (O) -O- (C 1 -C 4) - _{alkyl, - (C 1 -C 8)} - alkylsulfonyl, -C (O) -NH- (C ₁ -C ₈ ) -alkyl, -C (O) -N-[(C ₁ -C ₈ ) -alkyl] ₂ , -C (O) -NH ₂ , -S-R 10, -N (R 10) -C _{(O) -NH- (C 1 -C} 8) - and - [alkyl _{(C 1 -C 8) -]} 2, alkyl, or -N (R10) -C (O) -N R17 and R18 are the same or different independently of each other, a) hydrogen atom, _{b) - (C 1 -C 6} ) - alkyl, c)-(C ₆ -C ₁₄ ) -aryl- or d)-(C ₅ -C ₁₄ ) -heteroaryl, X is Cl, Br, I, triflate, nonaplate, tosylate, alkyl sulfonate or aryl sulfonate. The method of claim 1, A 1, A 2, A 3 and A 4 together with the two carbon atoms in formula I form benzene, pyrazine, pyridazine, pyridine, pyrimidine, triazine or tetraazine, Q is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₆ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; Phenyl, wherein said phenyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13; - (C ₁ -C ₄₎ - alkylene -O- (C ₁ -C ₄₎ - alkylene; - (C ₁ -C ₄₎ - alkylene -O-; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is acridinyl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, aze Thidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH Carbazolyl, carbolinyl, chromanyl, chromenyl, cinnaolinyl, decahydrocinnolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo [1,3,4] oxathiazinyl, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydro Furanyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indanyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isobenzofuranyl , Iscro Neyl, Isoindazolyl, Isoindolinyl, Isoindolinyl, Isoquinolinyl, Isothiazolyl, Isothiazolidinyl, Isothiazolinyl, Isoxazolyl, Isoxazolinyl, Isoxazolidinyl, 2- Isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadizolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 , 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,4-oxazepi Neyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phena Genyl, Phenothiazinyl, Phenoxatiinyl, Phenoxazinyl, Phtharazinyl, Piperazinyl, Piperidinyl, Pterridinyl, Furinyl, Pyranyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolyl , Pyrazolo [3,4-b] pyridine, pyridazinyl, pyri Oxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quino Nolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, Tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thia Diazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazoli Denyl, thiazolinyl, thienyl, thiethanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4 -Triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein the heteroaryl is unsubstituted or is mono-, di-, tri-substituted independently of each other by R13 Or tetrasubstituted), J is a covalent bond; — (C ₁ -C ₆ ) -alkylene, wherein said alkylene is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 14; -(C ₃ -C ₆ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14; Phenyl, wherein said phenyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as defined above and is unsubstituted or mono-, di-, tri-, or tetra-substituted independently of one another by R 13, R0, R1, R2, R3 and R4 are the same or different independently of each other, a) hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one, two or three times by R 13, c) F, Cl or Br, d) phenyloxy-, wherein the phenyloxy is unsubstituted or substituted once, twice or three times by R13, _{e) - (C 1 -C 3} ) - alkyl, fluoroalkyl, f) -N (R10) - ( C 1 -C 4) - alkyl (wherein the alkyl is unsubstituted or substituted once by R13, 2 times or 3 times), g) phenyl or naphthyl, wherein said phenyl or naphthyl is unsubstituted or mono-, di- or tri-substituted by R13, h) — (C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is as defined above and is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, i)-(C ₃ -C ₈ ) -cycloalkyl, wherein the cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, j) azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirin, di Oxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, Isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4- Oxazane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxetane, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole , Pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine , Thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thia Gin, 1,3-thiazole, thiazole, thiazolidine, thiazolin, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, Selected from 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13 3-7 membered cyclic residues, k) -O-CF ₃ , l) —O— (C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted once, twice or three times by R 13, m) -CN, n) -OH, o) -C (O) -R10, p) -C (O) -O-R11, q) -C (O) -N (R11) -R12, r) -N (R11) -R12, s) -N (R10) -SO ₂ -R10, t) -S-R10, u) -SO _n -R 10, where n is 1 or 2, v) -SO ₂ -N (R11) -R12, w) -SO ₂ -R13 or x) when at least one of A1, A2, A3 or A4 is a nitrogen atom, one of R1, R2, R3 or R4 is absent, R5 a)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted once, twice or three times by R13, b) F, Cl or Br, c) phenyloxy-, wherein said phenyloxy is unsubstituted or substituted once, twice or three times by R13, _{d) - (C 1 -C 3} ) - alkyl, fluoroalkyl, e) -N (R10) - ( C 1 -C 4) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13), f) phenyl or naphthyl, wherein said phenyl or naphthyl is unsubstituted or mono-, di- or tri-substituted by R13, g)-(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is as defined above and is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, h) — (C ₃ -C ₈ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R 13, i) azepine, azetidine, aziridine, azirin, 1,4-diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirin, di Oxazole, dioxazine, dioxol, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazoline, Isoxazole, isoxazolin, isoxazolidine, 2-isoxazolin, ketomorpholine, ketopiperazine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4- Oxazane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxaziridine, oxetane, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole , Pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrazine, tetrazole, thiadiazine , Thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-ti Gin, 1,3-thiazole, thiazole, thiazolidine, thiazolin, thienyl, thiethane, thiomorpholine, thiopyran, 1,2,3-triazine, 1,2,4-triazine, Selected from 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13 3-7 membered cyclic residues, j) -O-CF ₃ , _{k) -O- (C 1 -C 4} ) - alkyl (wherein the alkyl is unsubstituted or substituted once to three times by R13), l) -CN, m) -OH, n) -C (O) -R10, o) -C (O) -O-R11, p) -C (O) -N (R11) -R12, q) -N (R11) -R12, r) -N (R10) -SO ₂ -R10, s) -S-R10, t) -SO _n -R 10, where n is 1 or 2, u) -SO ₂ -N (R11) -R12 or v) -O-SO ₂ -R13, R 10 is a hydrogen atom, — (C ₁ -C ₃ ) -fluoroalkyl or — (C ₁ -C ₆ ) -alkyl, R11 and R12 are the same or different independently from each other, a) hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13, c) phenyl, wherein said phenyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R13; or d)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as defined above and is unsubstituted or mono-, di-, or tri-substituted independently of one another by R 13, R13 is F, Cl, -CN, = O, -OH,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, -CF ₃ , phenyloxy-, -C (O) -R10, -C (O) -O-R17, -C (O) -N (R17) -R18, -N (R17) -R18, -N (R10) -SO ₂ -R10, -S-R10, -SO _n -R10 where n is 1 or 2, -SO ₂ -N (R17) -R18, phenyl, wherein the phenyl is unsubstituted or is mono-, di- or trisubstituted independently of each other by R14 -(C ₅ -C ₁₄ ) -heteroaryl, wherein said heteroaryl is as defined above and is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14,-(C _3- C ₆ ) -cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 14, or a 3-7 membered cyclic moiety wherein said cyclic moiety is Unsubstituted or mono-, di-, or tri-substituted independently of one another by R14), and R14 is F, Cl, -OH, = O, -CN, -CF ₃ ,-(C ₁ -C ₈ ) -alkyl,-(C ₁ -C ₄ ) -alkoxy, -C (O) -OH,- N (R11) -R12, -C ( O) -O- (C 1 -C 4) - _{alkyl, - (C 1 -C 8)} - _{alkylsulfonyl, -C (O) -NH 2,} -C ( _{O) -NH- (C 1 -C 8} ) - alkyl, -C (O) -N - [ (C 1 -C 8) - _{alkyl] 2, -S-R10, -N} (R10) -C (O ) -NH- (C ₁ -C ₈ ) -alkyl or -N (R 10) -C (O) -N [(C ₁ -C ₈ ) -alkyl] ₂ , R17 and R18 are the same or different independently of each other, a) hydrogen atom, _{b) - (C 1 -C 4} ) - alkyl, c) phenyl or d)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as defined above, A process for preparing a compound of formula (I) wherein X is Cl, Br, I, triflate, nonaplate, tosylate, alkyl sulfonate or aryl sulfonate. The method according to claim 1 or 2, A 1, A 2, A 3 and A 4 together with the two carbon atoms in formula I form benzene or pyridine, Q is a covalent bond; - (C ₁ -C ₆₎ - alkylene; -(C ₃ -C ₆ ) -cycloalkyl; Phenyl, wherein said phenyl is unsubstituted or mono-, di-, tri- or tetra-substituted independently of one another by R13; - (C ₁ -C ₄₎ - alkylene -O- (C ₁ -C ₄₎ - alkylene; - (C ₁ -C ₄₎ - alkylene -O-; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is selected from pyridyl, quinolinyl, tetrahydropyranyl and thienyl, J is a covalent bond; - (C ₁ -C ₆₎ - alkylene; -(C ₃ -C ₆ ) -cycloalkyl; Phenyl; Naphthyl; Or-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as described above, R0, R1, R2, R3 and R4 are the same or different independently of each other, a) hydrogen atom, b)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted one to three times by R 13; c) F, Cl or Br, d) naphthyl, wherein said naphthyl is unsubstituted or substituted once, twice or three times by R13, e) phenyl, wherein the phenyl is unsubstituted or substituted once, twice or three times by R13, f)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as described above, g)-(C ₃ -C ₆ ) -cycloalkyl, _{h) -O- (C 1 -C 4} ) - alkyl, i) -CN, j) -OH, k) -C (O) -R10, l) -C (O) -O-R11, m) -C (O) -N (R11) -R12, n) -N (R11) -R12 or p) -O-SO ₂ -R13, R5 a)-(C ₁ -C ₄ ) -alkyl, wherein said alkyl is unsubstituted or substituted once, twice or three times by R13, b) F, Cl or Br, c) naphthyl, wherein said naphthyl is unsubstituted or substituted once, twice or three times by R13, d) phenyl, wherein the phenyl is unsubstituted or substituted once, twice or three times by R13, e)-(C ₅ -C ₁₄ ) -heteroaryl, wherein the heteroaryl is as described above, f)-(C ₃ -C ₆ ) -cycloalkyl, _{g) -O- (C 1 -C 4} ) - alkyl, h) -CN, i) -OH, j) -C (O) -R10, k) -C (O) -O-R11, l) -C (O) -N (R11) -R12, m) -N (R11) -R12 or n) -O-SO ₂ -R13, R 10 is hydrogen or — (C ₁ -C ₄ ) -alkyl, R 11 and R 12 are independently the same or different from each other, and are a hydrogen atom or — (C ₁ -C ₄ ) -alkyl wherein the alkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by R 13; , R 13 is F, Cl, —CN, —OH, — (C ₁ -C ₄ ) -alkoxy, —CF ₃ or phenyl, wherein the phenyl is unsubstituted or mono-, di- or tri-substituted independently of each other by R 14 ) R14 is F, Cl, -OH, -CN, -CF ₃ ,-(C ₁ -C ₄ ) -alkyl or-(C ₁ -C ₄ ) -alkoxy, A process for preparing a compound of formula I, wherein X is Cl, Br, I or tosylate. 4. A compound according to any one of claims 1 to 3, comprising: 3-benzyl-2-phenyl-2H-indazole; 2-phenyl-3-pyridin-2-ylmethyl-2H-indazole; 2-phenyl-3- (4-trifluoromethyl-benzyl) -2H-indazole; 2-phenyl-3- (4-methoxy-benzyl) -2H-indazole; 3- (6-methoxy-naphthalen-2-ylmethyl) -2-phenyl-2H-indazole; N, N-diisopropyl-2- (2-phenyl-2H-indazol-3-yl) -acetamide; (2-phenyl-2H-indazol-3-yl) -acetic acid tert-butyl ester; 3- (2,2-diethoxy-ethyl) -2-phenyl-2H-indazole; 3- (2,2-dimethyl-propyl) -2-phenyl-2H-indazole; 3-hexyl-2-phenyl-2H-indazole; 3-cyclopropylmethyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester; 3-benzyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester; 3-cyclopentylmethyl-2-phenyl-2H-indazol-6-carboxylic acid tert-butyl ester; Diethyl- [2- (2-phenyl-2H-indazol-3-yl) -ethyl] -amine; 2-phenyl-3- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -2H-indazole; 3-benzyl-2-phenyl-5-trifluoromethyl-2H-indazole; 3-benzyl-6-fluoro-2-phenyl-2H-indazole; 3-benzyl-4-methyl-2-phenyl-2H-indazole; 3-benzyl-6-methoxy-2-phenyl-2H-indazole; 3-benzyl-5-methoxy-2-phenyl-2H-indazole; Toluene-4-sulfonic acid 3-benzyl-2-phenyl-2H-indazol-6-yl ester; 3-benzyl-2-phenyl-2H-indazole-5-carboxylic acid; 3-benzyl-2-phenyl-2H-pyrazolo [4,3-c] pyridine; 3-benzyl-2- (4-methoxy-phenyl) -2H-indazole; 3-benzyl-2- (4-fluoro-phenyl) -2H-indazole; 3-benzyl-2- (2-fluoro-phenyl) -2H-indazole; 4- (3-benzyl-indazol-2-yl) -benzonitrile; 3-benzyl-2-naphthalen-1-yl-2H-indazole; 3-benzyl-2-pyridin-4-yl-2H-indazole; 4- (3-benzyl-indazol-2-yl) -quinoline; 3-benzyl-2-pyridin-4-yl-2H-indazol-6-carboxylic acid tert-butyl ester; 3-cyclopropylmethyl-2-pyridin-4-yl-2H-indazol-6-carboxylic acid tert-butyl ester; 3-benzyl-2-methyl-2H-indazole; 3-benzyl-2-phenethyl-2H-indazole; 3-benzyl-2-isopropyl-2H-indazole; Of benzyl-2-cyclohexyl-2H-indazole or 3-benzyl-2-thiophen-2-ylmethyl-2H-indazol-6-carboxylic acid tert-butyl ester Manufacturing method. 5. The preparation of compounds of formula I according to claim 1, wherein the transition metal catalyst is selected from the group of Pd-halides, Pd-halide complexes, Pd-phosphine complexes and Pd-alkene complexes. Way. The method of claim 5, wherein the transition metal catalyst is palladium (II) chloride, palladium (II) bromide, palladium (II) iodide, palladium (II) acetate, palladium (II) trifluoroacetate, tris (dibenzyl) Lidenacetone) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, bis (dibenzylideneacetone) palladium (0), bis (triphenyl-phosphine) palladium (II) chloride Or tetrakis (triphenylphosphine) palladium (0). The compound of formula I according to claim 1, which is carried out in the presence of a base selected from the group of carbonates, phosphates, fluorides, alkoxides and hydroxides with suitable metals or alkali metals as counter ions. Method for preparing the compound. 8. A process according to claim 7, wherein the base is selected from the group of potassium carbonate, potassium phosphate and cesium carbonate. The tri-butyl phosphine, tri-butyl phosphine tetrafluoroborate salt, tricyclohexyl phosphine, dicyclohexyl phenyl phosphine according to any one of claims 1 to 7, Methyldiphenylphosphine, dimethylphenylphosphine, trimethylphosphine, triethylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1 ' A process for the preparation of a compound of formula I, carried out in the presence of a ligand selected from the group of -biphenyl and 2,2'-bis (di-tert-butylphosphino) biphenyl. The N, N-dimethylformamide, N-methylpyrrolidinone, dimethylacetamide, dimethylsulfoxide, 1,2-dimethoxyethane, triethyl amine or pyridine according to claim 1. A process for the preparation of a compound of formula (I), which is carried out in the presence of a solvent selected from the group of: The process for preparing a compound of formula I according to claim 1, wherein the reaction between the compound of formula II and the compound of formula III is carried out in a temperature range of 60 to 150 ° C. 12.